Treatments for Parkinson's disease (PD) have historically focused on symptomatic relief, rather than therapies that alter the natural progression of the disease. Neurotrophic factors promote survival, differentiation, and maintenance of the nigrostriatal system and may have the potential to slow and reverse neurodegenerative processes. To date, exogenous administration of neurotrophic factors by gene therapy has been the most promising approach to ameliorate motor symptoms and stall disease progression. Preliminary studies have shown that viral vector-mediated overexpression in the nigrostriatal system of the neurotrophic factor pleiotrophin (PTN) provides neuroprotection and functional restoration in a 6-hydroxydopamine (6-OHDA) rodent model of PD. PTN is a potent cell survival and neurite outgrowth-promoting factor both in the developing and lesioned nigrostriatal system. PTN protein and receptors are expressed by mesencephalic dopamine (DA) neurons and are upregulated in response to striatal denervation and other nervous system injuries. PTN and its receptors are highly upregulated in the surviving nigral DA neurons of PD patients. Although PTN can protect SN DA neurons when administered prior to insult, morphological restoration and functional recovery after significant DA neuron loss are necessary for clinical application. Aim 1 will examine the therapeutic potential of PTN overexpression, generated by nigrostriatal injections of adeno-associated viral vectors encoding for PTN, following significant DA neuron and terminal loss by 6-OHDA. Aim 2 will test the therapeutic potential of PTN overexpression following significant DA neuron and terminal loss by -synuclein (-syn) overexpression. -syn rodent models exhibit -syn containing neuron bodies and dystrophic neurites that neurotoxin models fail to recapitulate. Neurotrophic factors that elicit positive effects in animal models mimicking both pathological hallmarks of PD, nigral cell death and Lewy body formation, have greater potential to be clinically beneficial to PD patients. The long-term goal of this proposal is to determine if PTN gene transfer can be used as a therapeutic strategy to treat PD after significant nigrostriatal damage has already occurred. The objective of this proposal is to determine the potential of PTN gene therapy to halt ongoing nigrostriatal degeneration and provide both morphological and functional restoration in rat models of PD. The central hypothesis is that overexpression of PTN in the damaged rat nigrostriatal system can facilitate long- term morphological and functional recovery in both the 6-OHDA and -syn parkinsonian models. These results may ultimately determine if PTN gene transfer can be used as a therapeutic option for PD and other nervous system disorders.